Pure Appl. Chem., Vol. 71, No. 3, pp. 369–376, 1999.
Printed in Great Britain.
q 1999 IUPAC
Paper 175
Stereoselective synthesis of three-membered
ring compounds via ylide routes
Li-Xin Dai†, Xue-Long Hou and Yong-Gui Zhou
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Fenglin Lu, Shanghai 200032, China
Abstract: Three types of small ring compounds (epoxides, aziridines and cyclopropanes) can
be synthesized stereoselectively via ylide route. Among them, the stereochemistry of
vinyloxiranes, vinylaziridines, cyclopropylesters, amides and ketones can be tuned by the
choice of reaction conditions and ylides with varying heteroatoms and ligands. Optically active
epoxides and acetylenylaziridines can be prepared via camphor-derived chiral sulfonium ylide
routes.
INTRODUCTION
Notwithstanding the fact that the appearance of the first phosphonium ylide may be traced back to one
hundred years ago, the term ylide was introduced by George Wittig in 1944 [1a]. The recognition of these
structurally interesting compounds as synthetically useful reagents was pronounced after the birth of the
Wittig reaction in 1953 [1b]. Since then, the chemistry of ylides flourished rapidly and they have now
become powerful and versatile synthetic tools [2] in the arsenal of organic chemistry.
An ylide can be viewed as a special carbanion which bears a neighboring positively charged
heteroatom. Ylides can undergo three types of reactions: olefination, cyclization to three-membered ring
(epoxidation, aziridination, and cyclopropanation), and rearrangement reaction. The reaction of ylides
with an electrophilic carbon atom of a C¼X (X¼O, C, N) bond (carbonyl compound, Michael acceptor or
imine) gives a betaine or oxetane intermediate. From this intermediate, elimination of the
heteroatomcontaining group can occur in either one of two different modes resulting in cyclization or
olefination. From this point, the use of an ylide is an alternative approach to that of the widely used
carbene or carbanion route in synthesizing these small-ring compounds. Among all kinds of ylides, the
phosphonium ylide was mainly used in olefination [1a,2], and the cyclization reactions are mainly carried
out with S, As, or Te ylides [1a,2]. A number of papers on ylide epoxidation and cyclopropanation have
been published, but stereochernical control of the reaction products still remains as a challenging
problem. In sharp contrast to ylide epoxidation and cyclopropanation, the ylide aziridination reaction is
rather undeveloped. Considering the importance of the small-ring compounds [3] in organic synthesis,
which have notable biological significance [4] and can undergo various chemical transformations, and in
conjunction with our experience of ylide chemistry [2] and transformations [5] of small-ring compounds,
we decided to explore the stereocontrolled and/or asymmetric synthesis of three-membered ring
compounds (Scheme 1) via the ylide cyclization route. In this paper, we would like to summarize our
findings on this facet.
EPOXIDATION VIA SULFONIUM YLIDE ROUTE
Epoxides are versatile intermediates in organic chemistry, the electrophilic or nucleophilic ring opening
reaction of them leads to 1,2-difunctionalized systems or to the formation of a new C–C bond [6]. The
*Lecture presented at the 5th International Conference on Heteroatom Chemistry (ICHAC-5), London, Ontario,
Canada, 5–10 July 1998, pp. 369–512.
†Corresponding author.
369
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L.-X. DAI et al.
Scheme 1
ylide LnMþCH – R route is a convenient and attractive method because ylides are generally easily
prepared and MLn can be recovered and reused.
Among various functionalized oxiranes, vinyloxirane has been shown to be one of the most important
synthetic intermediates [3,7]. Because of the known [2,3]-s-rearrangement, allylic sulfonium ylides have
found limited application in the preparation of vinyloxiranes. The successful use of a nonrearrangeable 3trimethylsilylated dimethylsulfonium allylide, generated by the deprotonation of corresponding
sulfonium salts, in the preparation of vinylaziridines [8] encouraged us to use the sulfonium salt as an
ylide precursor in the preparation of vinyloxiranes.
Under extremely mild conditions, aldehydes reacted smoothly with a silylated dimethylsulfonium
allylide, produced in situ from the corresponding dimethylsulfonium salt by solid KOH in acetonitrile, to
furnish the trans epoxide as the major product in excellent yield (eqn 1, Scheme 2). In the presence of
LiBr, the aldehyde reacted with a preformed ylide, generated in situ from the diphenylsulfonium salt and
KN(SiMe3)2 in THF at low temperature, to afford the epoxide in excellent yields and with very high cis
selectivity (eqn 2, Scheme 2) [9].
(1)
(2)
Scheme 2
The reactions shown in eqns 1 and 2 provide high stereoselectivity for the preparation of either trans or
cis-trimethylsilylvinyloxiranes in excellent yields. To our knowledge, both stereoisomers of
vinyloxiranes have not been obtained using the same ylide type. In addition, epoxidation with sulfonium
ylides has never been found to give preferentially the cis-isomers. It should be pointed out that the
addition of LiBr in the low temperature reaction (eqn 2) is crucial. Otherwise, an epoxide with a ratio of
trans:cis ¼ 2:1 would be obtained.
The possible intermediates in achieving either trans or cis-epoxides under different conditions might
be postulated as shown in Scheme 3. On using the dimethylsulfonium salt under phase-transfer
conditions, the reaction proceeded via intermediate A to furnish the thermodynamically stable trans
epoxides. With the diphenylsulfonium salt, the lithium salt changed the reaction path by coordination
with both the substrate and ylide through a halogen bridge. The reaction proceeded via the more favorable
transition state B to give an unstable intermediate C followed by an immediate antielimination of Ph2S to
furnish cis-epoxides.
The ylide route is also an alternative approach [3] to prepare optically active epoxides. From the same
starting material D-(þ)-camphor, chiral sulfides in which the sulfur atom was situated outside the ring and
oriented at the exo or endo position (Scheme 4) were prepared and used in one-pot asymmetric ylide
epoxidations. Epoxides with opposite asymmetric induction were obtained using either exo or endo
sulfides. When benzyl sulfides were used for asymmetric benzylidene transfer, a stoichiometric
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Stereoselective synthesis of three-membered rings
371
Scheme 3
epoxidation was realized with high ee values and the trans isomers were obtained exclusively. A catalytic
version of this reaction was achieved by employing methyl sulfides and high yields and
enantioselectivities were obtained [10].
Scheme 4
Using a similar method, optically active 2,3-epoxyamides [11] can be also synthesized via the
sulfonium ylide route (eqn 3, Scheme 5). The absolute configuration (2R, 3S) of the reaction product is
determined by chemical transformations.
(3)
Scheme 5
AZIRIDINATION VIA YLIDE ROUTE
The fact that azirdination via an ylide route has not been extensively explored may be rationalized by the
relatively low reactivity of common N-alkyl and N-arylimines toward nucleophilic attack as compared to
that of carbonyl compounds (for epoxidation) and a,b-unsaturated compounds (for cyclopropanation).
The low reactivity of an ordinary imine can be enhanced by either introducing an electron-withdrawing
group on the N-atom or by using a Lewis acid to activate the C¼N bond (Scheme 6).
Scheme 6
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L.-X. DAI et al.
Semiempirical AMI calculations indicated that the qualitative order of electrophlicity is PliCH¼NTs >
PhCH¼NDPP > PhCHO >> PhCH¼NPh [8]. Fortunately, activated N-tosylimines can smoothly react
with all kinds of semistablized sulfonium ylides (eqn 4, Scheme 7) under solid-liquid conditions [8,12].
The same reaction proceeds with As and Te allylides under low temperature, but the yields are poor. A
catalytic aziridination (eqn 5, Scheme 7) is also realized by employing a catalytic amount of Me2S under
solid-liquid phase transfer conditions [13].
(4)
(5)
(6)
(7)
Scheme 7
Stabilized sulfonium ylides can also react with N-tosylimines to afford the corresponding aziridines
[14] (eqn 6, Scheme 7) in high yields and poor trans/cis selectivity. Either trans or cis-Nphosphinoylvinylaziridines can be synthesized (eqn 7, Scheme 7) by the reaction of imines with the
corresponding allylides at low temperature or at room temperature in high yields and good to excellent
selectivities [15]. In all of the above reactions, a mixture of trans/cis isomers was obtained. After
numerous investigations, exclusive cis selectivity was achieved by the reaction of N-sulfonylimines with
propargylic ylides under phase-transfer conditions (eqn 8, Scheme 8) [16].
(8)
(9)
Scheme 8
The high stereoselectivity enables us to realize a reagent-controlled asymmetric aziridination by an
ylide route. Chiral sulfonium salts were synthesized by the reaction of camphor-derived chiral sulfides
with 3-bromo-l-trimethylsilylpropyne. Under solid-liquid phase transfer conditions, optically active
acetylenylaziridines were obtained in high yields and moderate to good ee values (eqn 9, Scheme 8).
Opposite asymmetric induction was achieved with sulfonium salts containing exo and endo-sulfido
groups. The absolute configuration was determined by chemical transformations. The exclusive cis
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Stereoselective synthesis of three-membered rings
373
selectivity may be explained by an intermediate formed by [2þ2] cycloaddition between the imines and
the ylides. [2þ2] cycloaddition is the rate-determining step. Due to steric hindrance, only the trans
intermediate was formed, then intramolecular trans elimination of dimethylsulfide to give cis aziridines.
Another chiral, sulfide-catalyzed asymmetric ylide aziridination also appeared in 1996 [17], which gave
high ee values and proceeded in a catalytic mode, albeit it requires strict reaction conditions and suffers
from low trans/cis selectivity (<3/1). The present asymmetric aziridination is a stoichiometric reaction
but may represent a promising general and practical approach to optically active aziridines due to its
compatibility with a wide range of substrates, high yields, and very mild reactions conditions.
Furthermore the ylide precursors could be recovered in higher than 80% yields without loss of optical
purity and could be resued.
The addition of carbenoids [18] or ylides to a C¼N double bond has been demonstrated as a synthetic
strategy for aziridination in recent years. However, the ylide and carbenoids methodologies can only be
applied to an activated imine, that is C¼N double bonds with an N-electron-withdrawing group, such as
p-tolylsulfonyl (Ts) [8,10,12,13,14,16], diphenylphosphinoyl (DPP) [15] or 2-(trimethylsilyl)ethylsulfonyl (SES) [17]. No report has appeared for the reaction of a nonactivated imine with a semistablized or
stablized ylide. Considering the vigorous conditions required for the deprotection and the difficulties in
the preparation of activated imines from certain carbonyl compounds, developing a general and facile
method for the aziridination of common N-alkyl and N-aryl imines is a challenge.
Encouraged by the successful activation of imines by Lewis acids in allylation reactions [19] and
aziridination [20] of BF3? OEt2 activated imines with ethyl diazoacetate, we examined the BF3? , OEt2 and
TMSCl activation of imines in the ylide reaction for the preparation of vinyl-and ethynylaziridines (eqn
10, Scheme 9). A variety of aromatic aldimines, either N-aryl or N-alkyl, could be aziridinated with good
to excellent yields, but aziridination failed when aliphatic aldimines were used as substrates. The
stereoselctivity of the aziridination is strongly dependent on the nature of the group on the nitrogen atom
of the imines: N-aryl aromatic aldimines gave purely the cis-aziridine, while N-alkyl aromatic aldimines
gave a mixture of cis and trans aziridines.
(10)
Scheme 9
CYCLOPROPANATION VIA YLIDE ROUTE
Vinylcyclopropanations are important compounds not only because they are versatile intermediates in
organic transformations and in the total synthesis of complex molecules, but also they form the
substructure of several biologically active natural compounds [3]. By retrosynthetic analysis, the addition
of allylic ylides LnMþCH – CH¼CHX to Michael acceptors is a convenient and attractive method because
the ylides are generally easily prepared and MLn can be recovered and reused. However, practical
methods for the synthesis of vinylcyclopropanes via the allylide route remains undeveloped.
The allylic telluronium ylides, generated in situ from the corresponding telluronium salts in the
presence of a lithium salt, reacted with a,b-unsaturated esters or amides to afford trans-2-vinyl-trans3substituted cyclopropyl esters or amides, respectively, with high selectivity and generally excellent
yields. In the absence of lithium salts, the stereoselectivity of these reaction changed to give cis-2-vinyltrans-3-substituted cyclopropyl esters or amides (Scheme 10). The selectivity of the two isomers can be
tuned from 99:1 to 1:99 [21].
The reaction mechanism might be postulated as shown in Scheme 10. We have qualitatively
determined that the Michael addition is a rate-determining step. In light of the well-accepted
mechanisly for ylide cyclopropanation [22], a possible mechanism for the reaction between the ylide and
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L.-X. DAI et al.
Scheme 10
the a,b-unsaturated esters or amides using KN(TMS)2 as the base is depicted in Scheme 10. The reaction
proceeded via a stable transition state 1 (TS-1) to give the product. While in the presence of LiBr, the
coordination of lithium salt might be an important factor. It has been demonstrated by Vedejs &
Schmidbauer [23] that some Lewis acids, such as MgBr2 and LiX, can coordinate with R3P¼CH2.
Recently, Armstrong [24] reported the structure of a single crystal of [Ph2P¼CH2-LiN(Bn)2]2 showing
the coordination of methylene phosphorane with lithium, and proposed that other heteroatom ylides might
also be potential Lewis base donors to alkali metal cations. Similarly, we think the lithium ion can
coordinate with both the ylidic carbon and the carbonyl oxygen of the esters or amides to form a sixmembered ring transition state (TS-2), which disposed Te(i-Bu)2 in a equatorial orientation due to steric
hindrance. A fast anti-elimination would give the corresponding product.
Contrary to the results obtained in the reaction of ylides with a,b-unsaturated esters or amides, we
found that by altering the base in the preparation of the ylide, the tuning of the stereochemistry failed in
the cyclopropanation reaction with a,b-unsaturated ketones. But by choosing different types of ylides, we
were able to tune the stereochemistry of the cyclopropanation reaction of a,b-unsaturated ketones. The
semistablized telluronium ylides reacted with a,b-unsaturated ketones to afford cis-2-vinyl-trans3substituted cyclopropyl ketones (eqn 11, Scheme 11) with high stereoselectivity and in high to excellent
yields [25]. Conversely, these enones gave trans-2-vinyl-trans-3-substituted cyclopropyl ketones (eqn
12, Scheme 11), when the corresponding arsonium ylides were employed.
(11)
(12)
Scheme 11
Highly electron-deficient vinyl and ethynylcyclopropane 1,1-dicarboxylic esters were conveniently
synthesized (eqn 13, Scheme 12) by the reaction of allylic diisobutyltelluronium ylides with alkylidene or
arylmethylidene malonic esters with high yields and high stereoselectivity [26].
CONCLUSION
The stereocontrolled methods described in this paper provide some facile and general means for the
synthesis of small-ring compounds. A salient feature is that the stereochemistry of the resulting small ring
compounds (epoxides, aziridines, and cyclopropanes) can be tuned at will by proper choice of reaction
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375
(13)
Scheme 12
conditions and ylides. In addition, optically active epoxides and aziridines can also be synthesized by
using camphor-derived chiral ylides. The role of the lithium salt and different type of ylides in the ylide
epoxidation and cyclopropanation is noteworthy. These features, together with the generality of these
methods and easy preparation of ylides, make these reactions valuable tools for organic synthesis.
ACKNOWLEDGEMENTS
Financial support from the National Natural Science Foundation of China (29790127) and the Chinese
Academy of Sciences are gratefully acknowledged. Many thanks are due to Dr An-Hu Li, Dr De-Kun
Wang, Dr Yong Tang, Mr Xiao-Fang Yang, and Mr Wei-Ping Deng for their contributions to the research
program of ylide cyclization.
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